Topical low-viscosity gel composition

ABSTRACT

A composition is provided that has a viscosity of less than about 15,000 cP and a pH of about 3.0 to 9.0 for treating a skin disorder in a human subject. The composition consists essentially of (a) a therapeutically-effective amount of at least one compound useful for treating such disorder, (b) a pharmaceutically-acceptable, lightly cross-linked polyacrylic acid polymer compatible with the compound, (c) optionally a water miscible solvent, (d) optionally a preservative, (e) optionally an oil phase component and suitable surfactant, and (f) water. The composition is useful for treating an inflammatory skin disorder, acne, or rosacea. The low viscosity composition has an advantage of being administered more accurately when combined with a container that administers the composition as drops.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to a composition for treating a skin disorder ina human, and a method of administering and preparing such composition.

2. Background

Skin disorders are a common problem in childhood, adolescence andadulthood. Skin disorders can include, for example, acne, inflammatorydiseases such as atopic eczema, or rosacea.

Acne vulgaris is a follicular disease characterized by pilosebaceousinflammations such as comedones, papules, pustules, cysts and nodules.Chiefly a disease of adolescence (and often a cause of emotionaldistress), acne originates endogenously and stems for multifactorialinfluences. Major progressive factors in the development acne includehyperkeratosis of the follicular epithelium, increased sebum production,and proliferation of Propionibacterium acnes. These factors areprimarily responsible for hyperkeratosis of the follicle lining,including retention of keratin and sebum, as well as the free fatty acidby-products of P. acnes metabolization which can lead to inflamed acnepapules and pustules.

Although acne may also be influenced by exogeneous and hormonal factors,research has been centered around eliminating P.acnes, the most commoncause of inflammation. To date, the pathogenesis of acne is not fullyunderstood, and there is currently no cure for the disease. Manysystemic and topical medications, such as tetracycline, have been usedto manage and control acne. None, however, is universally successful.

Acne treatment is typified by “polypharmacy”, whereby physiciansemployee simultaneous treatment with a variety of modalities. The searchfor improved acne treatments has been widespread and continuous duringthe past several decades. Enhanced cosmetic properties to encourage usercompliance, the use of topical therapies in place of systemic drugs toreduce toxicity and side effects, and the introduction of new drugs andformulations represent the forefront of acne treatment advances.

The first use of a topical antibiotic, erythromycin, for the treatmentof acne was reported by Fulton (Fulton, J. E. Jr. and Pablo, G. Topicalantibacterial therapy for acne. Study of the family of erythomycins.Arch. Dermatol. 110:83-86, 1974). Topical administration of these potentagents has the advantage of reduced side effects, particularly thosecaused by systemic drug effects, e.g., nausea, gastrointestinal upset,diarrhea, and vaginal yeast overgrowth.

Lincomycin antibiotics have been employed in the topical treatment ofacne (U.S. Pat. No. 3,969,516). Lincomycin was commercialized by UpjohnCo. (now Pharmacia & Upjohn) as Cleocin T Solution, Gel, Lotion andPledgets. Cleocin T Gel was an improvement over Cleocin T Solutionbecause of the elimination of alcohol and the ease of application to thefacial skin for the treatment of acne. This gel is based on carbomer934, NF.

Atopic dermatitis is a polygenic disease with an inherited predelectionand strongly influenced by environmental factors. The condition affectsinfants, children, adolescents and adults and is allergic in nature. Thedistribution is symmetrical, typically involving the face, neck andflexural areas. Atopic dermatitis is chronic, relapsing and usuallypruritic. Topical treatment frequently includes topical corticosteroids,such as desonide, hydrocortisone valerate, fluocinolone acetonide,triamcinolone acetonide, betamethasone valerate, hydrocortisonebutyrate, halobetasol propionate, betamethasone dipropionate, clobetasolpropionate, difloransone diacetate, fluticasone propionate, budesonideor the like.

Rosacea is a chronic inflammatory eruption of the nose, face and otherflushing areas of the skin. The disease is most common in middle agedwomen and is characterized by erythema, papules, pustules,telangiectasia and enlarged sebaceous glands. The cause etiology is nottotally clear; however vasomotor lability and menopause are predisposingfactors. The organism Demodex folliculorum is found frequently in thecontents of inflamed pustular follicles, and has a possible role in thisskin disorder. Treatments include topical metronidazole and oraltetracycline type antibiotics.

SUMMARY OF THE INVENTION

One aspect of this invention is a composition having a pH of about 3.0to about 9.0 and a viscosity of less than about 15,000 centipoise (cP)for treating a skin disorder in a human subject. The compositioncomprises (a) a therapeutically-effective amount of at least onecompound useful for treating such disorder, (b) apharmaceutically-acceptable polyacrylic acid polymer compatible with thecompound, (c) optionally a water miscible solvent, (d) optionally apreservative, (e) optionally an oil phase and surfactant, and (f) water.

Another aspect of the invention is a composition described above incombination with a container that accurately administers a portion ofthe composition for topical administration to a patient.

Another aspect of the invention is a composition described above incombination with labeling instructions for use in treating the skindisorder.

Still another aspect of the invention is a method for treating a skindisorder in a human subject, which method comprises administering acomposition described above to an affected area of the subject's skinhaving such disorder in an amount and for a period of time sufficient toimprove the skin disorder.

Still another aspect of the invention is a method for preparing acomposition of this invention by combining water with atherapeutically-effective amount of a suitable compound and the polymerand optionally a water-miscible solvent and preservative. If a lotion isdesired an oil phase is formed for integration with the aqueous phase.

Other aspects of the invention may be apparent upon further reading thespecification and claims of the patent application.

SPECIFIC DESCRIPTION

This invention provides a novel topical gel or lotion delivery systemfor the treatment of skin diseases, particularly acne vulgaris. Oneunique aspect of the system is the use of a polymeric material thatprovides a gel material that has a very low viscosity but which iscosmetically elegant and aids in the administration process by providinga pourable composition that flows through a dropper tip easily.

The Composition

One aspect of this invention is a composition having a pH of about 3 toabout 9 and a viscosity of less than about 15,000 cP for treating a skindisorder in a human subject. The composition comprises atherapeutically-effective amount of at least one compound useful fortreating such disorder, a pharmaceutically-acceptable, lightlycross-linked polyacrylic acid polymer compatible with thetherapeutically-effective compound, optionally a water miscible solvent,optionally a preservative, and water. The composition may include asolution of the active compound or a suspension. A lotion will alsoinclude a pharmaceutically-acceptable oil phase emulsified with one ormore surfactants.

The composition is useful to treat skin disorders, e.g. acne, rosacea,or inflammatory skin diseases such as atopic dermatitis. The compositionwill include an active agent that will be one compound alone or two ormore compounds in combination. The active agent can be an antibiotic, acorticosteroid, a retinoid, an anti-inflammatory imidazole, anon-steroidal anti-inflammatory agent (NSAID), or a combination.

An antibiotic is generally viewed as a drug that inhibits the growth ofan unwanted microorganism. Representative examples of topicalantibiotics include lincomycins, (e.g. clindamycin), erythromycin,minocycline, and tetracycline, and the pharmaceutically-acceptablesalts, esters, or prodrugs thereof. Preferred is clindamycin phosphate.

A “retinoid” is a keratolytic drug related to retinoic acid andgenerally includes chemical entities such as retinol and its esters andclosely related naturally-occurring derivatives and structurally-relatedsynthetic analogs. This includes, for example, retinol, retinal,tretinoin (all-trans retinoic acid), isotretinoin, adapalene(6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid), and the like. Ofthese, tretinoin is preferred.

Generally, a topical corticosteroid is a compound that is a structuralmodification of hydrocortisone (also known as cortisol) and that showstopical anti-inflammatory activity. Representative examples includethose set forth in Table 65-1 at page 1575 of “Goodman & Gilman's ThePharmacological Basis of Therapeutics,” Eighth Edition, McGraw-Hill,Inc. (1993). Specific, non-limiting examples of topical cortiocosteroidsinclude those mentioned in the “background” section of this application.Preferred corticosteroids, when used as a single active agent, includediflorasone diactetate, fluticasone propionate, halobetasol priopionate,or budesonide. Halobetasol propionate is most preferred when used as asingle active ingredient.

Nonsteroidal anti-inflammatory agents (NSAIDs) are compounds thatsuppress the inflammatory response when topically applied by inhibitingprostaglandin synthesis or by other mechanisms of action. Examples maybe found in Goodman and Gilman, Ibid. Representative examples includeibuprofen, indomethacin, diclofenac, and naproxen and their salts.Preferred is diclofenac.

An anti-inflammatory imidazole is an imidazole compound that suppressesa topical inflammatory response. Metronidazole is a representativeimidazole compound suitable for this invention.

In describing the details of the composition, the numerical ranges givenherein are those amounts that provide the functional results in thecomposition. Thus, the ranges are generally introduced with the term“about” to indicate a certain flexibility in the range, i.e. ±10% orless at the lower and upper numerical ranges given.

As mentioned, the active agent may be present alone or in combination.For example, a topical antibiotic, such as clindamycin phosphate, may becombined with a topical corticosteroid. Where a formulation is designedprimarily for application to the facial area, to treat acne for example,it is preferred to combine an antibiotic (e.g. clindamycin phosphate)with a less potent corticosteroid, such as desonide, hydrocortisonevalerate, fluocinolone acetonide, hydrocortisone butyrate, ortriamcinolone acetonide. The topical antibiotic can also be combinedwith a retinoid, e.g clindamycin phosphate and tretinoin or adapalene.

The composition of the invention will include a polymeric material thatwill be present in an amount sufficient to bring the viscosity of thecomposition to a level of not more than about 15,000 cP, preferablybetween about 100 and about 12,000, and more preferably between about300 and about 10,000. The viscosity is determined at room temperature(20-25° C.) using a Brookfield viscometer model DV-I+, spindle #27 at 12revolutions per minute (rpm). If the measured viscosity is less than4,000 cP, spindle #21 should be used instead of #27. By keeping theviscosity below about 15,000 cP, the advantages of more appealingcosmetic characteristics and ease of accurate application throughimproved flow and pourability are achieved.

The polymers that have been found to be particularly useful in thecomposition of the present invention are lightly cross-linkedpolyacrylic acid polymers which are available from B.F. Goodrich underthe tradename CARBOPOL®. They are generically referred to as carbomers.The CARBOPOL polymers are hydrophilic polymers based on a polyacrylicacid structure. For use in the present invention the lightlycross-linked polymers include CARBOPOL 910, 941,971, and 981 andCARBOPOL ETD 2050.

Either CARBOPOL 941 or 981 is particularly valuable for the presentinvention because the viscosity of a gel based on CARBOPOL 941 or 981 islow relative to its concentration. This feature is the result of the lowlevel of cross-linking within the polymer structure in a neutralizedaqueous system. In contrast polyacrylic acid polymers which display ahigh level of cross-linking, such as CARBOPOL 980 or 974P, produce gelswith higher viscosity at comparable concentrations.

A 0.5% solution of either CARBOPOL 941 or 981 at pH 7.5 has a viscositymeasurement of from 4,000 to 11,000 cP (Brookfield viscometer at 20 rpm)compared to a viscosity measurement of from 40,000 to 60,000 cP for acomparable 0.5% solution of either CARBOPOL 940 or 980 (reference: B.F.Goodrich Product Guide, Bulletin 2).

This lower-level viscosity feature of the lightly cross-linkedpolyacrylic acid polymers, e.g. CARBOPOL 941 and 981, offers twoadvantages to the composition of the present invention. A gel made fromone of these lightly cross-linked polymers provides better skin feel andlubricity than a gel of comparable viscosity made from a highlycross-linked polymer. Second, a low viscosity gel can be administeredvery accurately by a dropper or drip-type dispenser as compared to othercommercial products which are thicker gels that do not provide asaccurate an application.

CARBOPOL 941 NF resin and its cosolvent polymerized alternative,CARBOPOL 981 NF resin, provide permanent emulsions and suspensions atlow viscosities. The gels produced with these resins have excellentclarity. In ionic systems, they perform better than most of the otherCARBOPOL resins and at concentrations below 1.5% in solvent systems. Thepolymers are available from B.F. Goodrich Specialty Chemicals, 9911Brecksville Road, Cleveland, Ohio 44414-3247.

CARBOPOL resins are polymers of acrylic acid crosslinked withpolyalkenyl ethers or divinyl glycol. The polymers are flocculatedpowders of primary particles averaging about 0.2 micron in diameter. Theflocculated powders are agglomerates that average 2 to 7 microns asdetermined by Coulter Counter. These agglomerates cannot be broken downinto the primary particle once produced.

Each primary particle can be viewed as a network structure of polymerchains interconnected by crosslinks. Without the crosslinks, the primaryparticle would be a collection of linear polymer chains intertwined butnot chemically bonded. These linear polymers are soluble in a polarsolvent, such as water. They swell in water up to 1000 times theiroriginal volume (and ten times their original diameter) to form a gel,especially when exposed to a pH environment above about 4-6. Since thepK_(a) of these polymers is 6.0±0.5, the carboxylate groups on thepolymer backbone ionize, resulting in repulsion between the negativeparticles, which adds to the swelling of the polymer. Highly crosslinkedpolymers of this type do not dissolve in water, rather they form gels byforming homogeneous dispersions.

The glass transition temperature of CARBOPOL resin is 105° C. (221° F.)in powder form. However, the glass transition temperature dropsdramatically as the resin comes into contact with water. The polymerchains start gyrating and the radius of gyration becomes bigger andbigger. Macroscopically, this phenomenon manifests itself as swelling.

The aqueous composition of the invention, will optionally include awater miscible solvent and a preservative. The water miscible solvent(i.e. a cosolvent) will be present if needed, to assist in dissolvingthe active agent. The cosolvent may be a single component or a mixture.Examples include those that are miscible with water such as ethanol,propylene glycol, glycerin, polyethylene glycol 400, and the like.Certain water-miscible solvents, such as glycerin or propylene glycol,also add beneficial humectant properties to the composition. Drugdelivery and penetration into the skin can be modified by thewater-miscible cosolvent composition.

The preservative useful in the composition is material that aids inensuring a stable composition and/or prevents growth of bacteria. Thus,a preservative may be one or more of an antioxidant, a chelator, anantibacterial, or the like. Suitable preservatives includemethylparaben, butylparaben, propylparaben, benzyl alcohol, sorbic acid,imidurea, thimerisal, propyl gallate, BHA, BHT, citric acid, disodiumedetate, and the like. Another optional additive is a fragrance.Generally, this will be present in a trace amount only and has no effecton the functioning of the composition.

A preferred composition, particularly for the treatment of acne, willexhibit a pH of about 3 to 9, preferably about 4 to 7, and mostpreferably at about 5 to 6. Thus, the composition may also include apH-adjusting agent as needed at a level to adjust the pH to the desiredrange. Such agents include many pharmaceutically-acceptable organic orinorganic bases, e.g., sodium hydroxide and tromethamine. The pH chosenwill depend in part on the pH tolerance of the active agent chosen forthe composition. The examples provide guidance for certain compounds andsuitable pH values for the compositions.

Another aspect of this invention is an emollient embodiment, i.e., afluid emulsion or lotion. This aspect of this invention is a compositionhaving an internal oil phase dispersed with the aid of at least onesurfactant, e.g. an emulsifier, in water. Suitable surfactants are wellknown in the art and include those referred to as anionic and nonionicagents. These are described in Remington: The Science and Practice ofPharmacy, Nineteenth Edition, Vol. 1 at p. 251. Representativesurfactants include polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, sorbitan laurate, sorbitan oleate, sorbitan stearate,polyoxyethylene stearate, sodium laureth sulfate, and laureth-10. Oilphase components include those that are commonly used in the art such asmineral oil, petrolatum, stearyl alcohol, cetyl alcohol, isopropylmyristate, diisopropyl adipate, stearic acid, white wax, and the like.

The following Table sets forth operational and preferred ranges of thevarious components for a gel composition having an active ingredient,which may be a single compound or a combination of two or morecompounds. The term surfactant means one or more surfactants, whichincludes wetting agents and emulsifiers.

TABLE A % w/w Component Operational Preferred More Preferred Activeingredient 0.005-10.0 0.01-5.0 0.05-2.0  Polyacrylic Polymer Acid0.05-3.0 0.05-1.0 0.1-0.5 Cosolvent  0.0-70.0  0.0-40.0  0.0-25.0Preservative  0.0-3.0 0.01-1.0 0.05-0.25 Surfactant*  0.0-8.0  0.0-5.00.0-3.5 Oil phase*  0.0-50.0  0.0-25.0  0.0-15.0 Water QSAD 100 QSAD 100QSAD 100 Base QS pH QS pH QS pH *Present for lotion

The following Table B sets forth the operational, preferred, and morepreferred concentrations of representative active ingredients that canbeneficially be used in practicing our invention, whether alone or incombination. The exact amount will be readily determined by one ofordinary skill by referencing standard texts such as the Physicians DeskReference or Goodman and Gilmann's referred to hereinbefore.

TABLE B % w/w Component Operational Preferred More Preferred Antibiotic0.1-5.0 0.5-2.0  0.5-1.0 Corticosteroid 0.005-2.5  0.01-1.0  0.05-0.1Retinoid 0.005-0.5  0.05-0.1  0.025-0.05 Imidazole 0.1-5.0 0.5-2.00.75-1.0 NSAID 0.1-3.0 0.2-2.0  0.2-1.0

To make an emulsion (i.e., lotion) form of our invention as broadly setforth in Table A, the surfactant and oil phase component are included inthe composition. The following table illustrates the manner in which thecomposition is modified to form a lotion.

TABLE C % w/w Component Operational Preferred More Preferred Surfactant0.1-8.0  0.5-5.0  1.0-3.5  Oil phase 1.0-50.0 2.5-25.0 5.0-15.0

The preferred formula of the composition would either bepreservative-free or have a decreased level of preservatives as comparedto material that is commercially available. This is important becausethe presence of preservatives in a composition can result in irritationor allergic reaction of the skin. Reducing the possibility of skinirritation or allergic reaction in a composition provides a betterproduct. Regarding compositions that contain clindamycin phosphate, theleading product is Cleocin T Gel. It is a clear viscous gel that testshave shown is not as well accepted as the less viscous material of theinvention made with a more lightly cross-linked polymer. By controllingthe viscosity of the gel at a low level it can be accurately dispensedfrom a clear plastic squeeze bottle rather than from an ointment tube.The advantage is two-fold. One is accurate dosage control by using areduced orifice tip and improved product presentation for marketing. Inaddition, tests have shown that the less viscous material iscosmetically more elegant and will result more regular use.

In preparing a composition of this invention general formulationtechniques known in the art of pharmaceutical science will be used. See,for example, Remington: The Science and Practice of Pharmacy, NineteenthEdition, Mack Publishing Company (1995). Preparation of specificformulations may be found in the examples.

To prepare a gel with two active ingredients where one is suspended andthe other is dissolved, first add the insoluble active to awater-miscible ingredient, or a portion of the water with a surfactant,to disperse. Separately, dissolve the other active and any otherpreservative ingredients in the purified water. Disperse the gellingagent in the aqueous solution with appropriate stirring. Then add thedispersion of the first active ingredient to the gel and mix well toblend. Last, add a pH adjusting agent to adjust the pH to the desiredrange. The preparation of a gel when both active ingredients aredissolved is similar, varying only in the first step. First, add theactive with lower aqueous solubility to a solvent, blend of solvents, orwater. Mix to dissolve. Separately, dissolve the other active and anypreservative ingredients in the purified water. Disperse the gellingagent in the aqueous solution with appropriate stirring. Then add thesolution of the first active to the gel and mix well to blend. Last, adda neutralizing agent to adjust the pH to the desired range.

For a combination of an antibiotic e.g. clindamycin phosphate with aretinoid, such as tretinoin, three formulation approaches can be appliedto a composition of the invention: 1) an aqueous gel, formed from alightly crosslinked carbomer gelling agent, with the clindamycinphosphate dissolved and the tretinoin suspended; 2) an oil-in-wateremulsion with the clindamycin phosphate dissolved in the water thickenedwith a lightly cross-linked carbomer gelling agent and the tretinoindissolved in an internal liquid oil phase; and 3) a solution consistingof water and water-miscible organic solvents with the clindamycinphosphate and tretinoin both dissolved.

The following compositions are given as representative as the types ofcompositions useful in this invention.

Where the composition contains an antibiotic alone, for exampleclindamycin phosphate, the composition has a pH of about 4 to 7 andcontains

(a) about 0.5% to 2.0% w/w clindamycin phosphate,

(b) about 0.1% to 0.4% w/w of the polymer,

(c) the base to adjust pH,

(d) about 15.0% to 25.0% w/w of a water miscible solvent,

(e) less than about 0.2% w/w of a preservative, and

(g) QSAD purified water to 100% w/w.

Preferably such a composition has a pH of about 5 to 6 and contains

(a) 1.0 to 1.5% w/w clindamycin phosphate,

(b) 0.2% w/w of the polymer,

(c) the base to adjust pH,

(d) 15.0% w/w propylene glycol and 5.0% w/w polyethylene glycol 400,

(e) 0.1-0.15% w/w methylparaben, and

(g) QSAD purified water to 100% w/w.

A gel composition where the antibiotic in clindamycin phosphate and theretinoid is tretinoin may contain

(a) (i) about 0.5% to about 2.0% w/w clindamycin phosphate, and

(ii) about 0.01% to about 0.05% w/w tretinoin;

(b) about 0.1% to about 0.5% w/w of the polymer;

(c) the base to adjust pH;

(d) about 10% to about 30% w/w of a water-miscible solvent;

(e) less than about 0.2% of a preservative; and

(g) QSAD purified water 100% w/w.

A lotion composition of clindamycin phosphate and tretinoin usefullywill contain

(a) (i) about 0.5% to about 2.0% w/w clindamycin phosphate and

(ii) about 0.01% to about 0.05% w/w tretinoin;

(b) about 0.1% to about 0.5% w/w0 of the polymer;

(c) the base to adjust pH;

(d) about 5% to about 30% w/w of a water-miscible solvent;

(e) less than about 0.2% of a preservative;

(f) an oil phase in combination with at least one surfactant to form anemulsion; and

(g) QSAD purified water 100% w/w.

Treatment

Another aspect of the invention is a method for treating a skin disorderin a human, which method comprises administering a composition to anaffected area of the subject's skin having such disorder in an amountand for a period of time sufficient to improve the skin disorder,wherein the composition is described in this patent application.Preferably, the composition is administered once a day over thetreatment period. Depending on the patient's improvement, the treatmentmay extend for less than a week to two months or more. The progress ofimprovement may be monitored by the patient or by a physician.

The skin disorders which are treatable with the composition of theinvention include acne vulgaris, rosacea, and various inflammatoryconditions including atopic dermatitis. A discussion of these conditionsmay be found in the Merck Manual. For example, acne vulgaris is aninflammatory disease affecting hair follicles and sebaceous glands.Lesions are most common on the face, but the neck, chest, upper back,and shoulders may also be affected.

The affected area of the subject's skin can be anywhere on the body inwhich the skin disorder exists. The amount of composition and period ofadministration time sufficient to improve the skin disorder will bedependent on the subject and skin condition. Generally, a sufficientamount will be squeezed from a dropper tip of a squeeze bottle or an eyedropper onto the area affected and rubbed gently into the skin. Usually,no more than a few drops will be needed to apply to an affected area.

Article of Manufacture

Another aspect of the invention is an article of manufacture thatcomprises a composition for treating a skin disorder as described abovein a suitable container, preferably in a dropper bottle, in combinationwith labeling instructions. The dropper bottle can be made of anymaterial, for example, glass, rigid plastic, or flexible plastic. Othermeans of administration are an eyedropper, or tube with a suitable smallorifice size, such as an extended tip tube.

The composition of this invention may be, for example, filled andpackaged into a plastic squeeze bottle (i.e., 42 g). A suitablecontainer-closure system for the package presentation for thecomposition described in Table D.

TABLE D NOM- INAL OVERFLOW MANUFAC- SIZE CAPACITY MATERIAL DESCRIPTIONTURER 1 oz 46 cc Natural cylinder, round Wheaton polypropylene bottle,15/415 Plastic finish, Wheaton B-21411 Products White low densitypolyethylene 1101 15 mm dropper tip plug, Wheaton Wheaton B-11048 AvenueWhite polypropylene extended Milville, NJ tip closure, Wheaton B-1504408332

The labeling instructions can come in the form of a pamphlet, a labelapplied to or associated with the packaging of the article ofmanufacture.

The labeling instructions provide for administering a composition of theinvention to an affected area of a subject's skin having a skindisorder, in an amount and for a period of time sufficient to improvethe skin disorder. Printed labeling instructions are functionallyrelated to the composition of the invention inasmuch as such labelinginstructions describe a method to treat a skin disorder. The labelinginstructions are an important aspect of the invention in that before acomposition can be approved for any particular use, it must be approvedfor marketing by the United States Food and Drug Administration. Part ofthat process includes providing a label that will accompany thepharmaceutical composition which is ultimately sold. While the labelwill include a definition of the composition and such other items suchas the clinical pharmacology, mechanism of action, drug resistance,pharmacokinetics, absorption, bioavailability, contraindications and thelike, it will also provide the necessary dosage, administration andusage. Thus, the combination of the composition with the dropper bottlewith appropriate treatment instructions is important for the properusage of the drug once it gets on the market. Such treatmentinstructions will describe the usage in accordance with the method oftreatment set forth herein before.

Having now generally described this invention, the same will be betterunderstood by reference to certain specific examples which are includedherein for purposes of illustration only and are not intended to belimiting of the invention or any embodiment thereof, unless sospecified.

In the following examples, the viscosity is determined at roomtemperature (20-25° C.) using a Brookfield viscometer model DV-I+,spindle #27 at 12 revolutions per minute (rpm). If the measuredviscosity is less than 4,000 cP, spindle #21 should be used instead of#27.

EXAMPLES Example I

This example sets forth a pourable gel composition of this invention.The procedure set forth in steps a-f produces a composition according toTable I. The composition is referred to as “Clindagel.” An applicationto designate Clindagel as a trademark has been filed.

TABLE I COMPONENT % w/w Clindamycin phosphate, USP (equivalent to 1.191% clindamycin) Methylparaben 0.15 CARBOPOL ® 941 (or 981) 0.20Propylene glycol 15.0 Polyethylene glycol 400 5.0 Sodium hydroxide (10%solution) QS pH 5.3 to 5.7 Purified water QSAD 100.00

The viscosity of this composition is about 1,000 cP.

a. Weigh approximately 90% of the purified water into a stainless steelkettle. Add the propylene glycol and polyethylene glycol 400. Stir withpropeller mixer.

b. At room temperature add methylparaben to step a) with continuedstirring. Mix until dissolved.

c. While continuing to mix, add clindamycin phosphate to step b). Mixuntil dissolved.

d. While continuing to mix, add CARBOPOL® 981 or 941 slowly to step c),avoiding clumping. Mix vigorously at room temperature until a uniformand lump-free dispersion is achieved.

e. While mixing, add sufficient sodium hydroxide, 10% solution, toachieve a pH of 5.3 to 5.7. Mix until uniform.

f. Add the remaining water to make 100% and mix until uniform.

Example II

This example shows the composition of a commercially available productcontaining clindamycin phosphate. The product is sold by Pharmacia asCleocin T® Gel. The components and amounts were analyzed to be asfollows:

TABLE II COMPONENT % w/w Clindamycin phosphate  1.19 Carbomer 934 P 0.8Propylene glycol 4.9 Polyethylene glycol 400 10.2  Sodium hydroxide QSpH 5.4 Methylparaben 0.3 Allantoin 0.2 Purified water QSAD 100

The viscosity of this composition is about 20,000 cP.

Example III Comparison of Clindagel and Cleocin-T® Gel

This example provides clinical data showing the advantages of acomposition of the invention as compared to a known commercialcomposition.

A multi-center investigator-blind clinical trial was conducted comparinga composition of this invention (see Example I) Clindagel, once daily,and Cleocin-T® Gel (see Example II), twice daily (according tomanufacturer's directions), in acne vulgaris. Three hundred and twentyfour patients, half in each group, were treated for up to 12 weeks. Theinvestigator was “blinded” in that she/he did not know which treatmentthe patient used before the investigator evaluated the condition of thepatient's acne.

Evaluations included inflammatory lesion count, total lesion count,physician's global assessment and skin-related side effects. Papules andpustules were considered inflammatory lesions. Total acne lesionsincluded open and closed comedones in addition to inflammatory lesions.The physician's global severity assessment was based on a nine-pointscale. At study end (12 weeks or last evaluation) it was concluded thatClindagel used once a day was equal in effectiveness to Cleocin-T® usedtwice daily and Clindagel had significantly fewer side effects. The dataon lesion counts are summarized in Table III.

TABLE III Improvement in Acne Lesions at Endpoint: Clindagel ™ OnceDaily vs. Cleocin-T Gel Twice Daily. Clindagel ™ Cleocin-T ® Gel OnceDaily Twice Daily Percent Change from Baseline 95% Confidence ACNELESIONS (standard deviation) Lower Bound Inflammatory −50.90 (2.62)−50.02 (2.62) 0.897 Total −37.27 (2.44) −39.52 (2.44) 0.801

The physician's global assessment is summarized in Table IV.

TABLE IV Summary of Number of Patients with a Two-Category Improvementfrom Baseline in the 9-Point Physician's Global Severity Assessment atEndpoint PHYSICIAN'S Clindagel ™ Cleocin-T  ® Gel GLOBAL Once DailyTwice Daily 95% Confidence Assessment Number of Patients Lower BoundImproved by 2 84 84 0.833 categories Same or Worsened 72 73 TOTAL 156157

The frequency of dermal side effects from Clindagel™ once daily and fromCleocin-T® twice daily are tabulated in Table V.

TABLE V Summary Results of Frequency of Adverse Events ComparingClindagel ™ Once Daily and from Cleocin-T ® Twice Daily. ADVERSE EVENTSClindagel ™ Cleocin-T ® Gel Fisher's Category Once Daily Twice DailyExact Test Number of patients 168 165 in safety evaluation Number ofpatients 2 13 0.003 with at least one skin/appendage disorder reportedFrequency of local 1.2% 7.9% adverse reactions

Example IV

This example sets forth the results of a user preference test (withvehicles, not actives) comprising a composition of this invention isshown in Example I (with CARBOPOL® 981) with the commercially availablecomposition of Example II, (with Carbomer 934 P). Table VI sets forththe formulation compositions.

The study was conducted amongst a normal subject patient population of10 in order to evaluate the functional and cosmetic attributes using ahalf-face, paired, and symmetrical design.

TABLE VI Component % w/w Vehicle Formulae: Clindagel Cleocin-T GelCarbomer 934P — 0.8 Carbomer 981 0.2 — Propylene glycol 15.0  4.9Polyethylene glycol 400 5.0 10.2  Sodium hydroxide qs to pH 5.5 qs to pH5.4 Methylparaben  0.15 0.3 Allantoin — 0.2 Purified water QSAD 100 QSAD100

Test articles (gel vehicles) were identified by blinded identificationcode, thereby preventing test subject from knowing the identity of thetest articles being applied. Each test pair involved test articles L vs.R, which were used on the left and right sides of the face respectively.The test articles assigned to L and R codes were varied so that eachtest article was randomly evaluated on R and L test locations and byorder of application.

The subjects were equally balanced for sex. The mean age of thepopulation was 34 years old within an age range of 25-44 years.

The following attributes were assessed during and after application:spreadability, feel/texture during application, ease of application,ability to rub the gel into the skin, drying time on the skin, skin feelafter application, overall cosmetic preference, and usability of theproduct. Each gel was evaluated for its functional and cosmeticattributes on a scale of 1-6, with 1 being Unacceptable and 6 beingExcellent.

Of the nine subjects with a preference for one of the test articles, 67%preferred Clindagel vehicle over Cleocin-T vehicle. The degree ofpreference of Clindagel over Cleocin-T was judged “moderate” to “great”in 100% of those tested. The data are tabulated in Table VII.

TABLE VII Vehicle Preference By Subject Subject 1 2 3 4 5 6 7 8 9 10TOTAL Age 26 39 44 42 25 28 42 35 33 26 Sex F F M M F F M F M MCleocin-T P P P NP 3 Clindagel P P P P P P NP 6 P = Preferred NP = NoPreference F = Female M = Male

There was a significantly higher score for Clindagel vehicle than forCleocin-T gel vehicle in four of the specific attributes, and nosignificant difference in two of those attributes (Table VIII).Clindagel vehicle scored marks of “Very Good” in three of the sixattribute categories and marks of “Good” in three other. Cleocin-T gelvehicle scored marks of “Very Good” in one category, “Good” in fourcategories and “Fair” in one category.

TABLE VIII Frequency of Higher Score of Clindagel Vehicle and Cleocin-TGel Vehicle Functional and Frequency of Higher Score (%) No CosmeticAttribute: CLINDAGEL CLEOCIN-T Preference Spreadability 30% 30% 40%Feel/texture during 50% 30% 20% application Ease of application 20% 30%50% Ability to rub gel into skin 50% 20% 30% Length of drying time 70%20% 10% Skin feel after application 50% 30% 20%

Forty percent of test subjects commented independently that theClindagel vehicle was “runny” or “waterey” upon application. This wasalso reflected in the “Ease of Application” attribute, where Cleocin-Thad a slightly higher score. 50% of test subjects commentedindependently on their face feeling “sticky” after application of theCleocin-T vehicle. 80% of test subjects indicated that they would usethe Clindagel vehicle as a facial medication product. Only 30% of thosetested indicated that they would use Cleocin-T vehicle as a facialmedication product.

Example V Stability Study of Clindagel™ with Clindamycin Phosphate asActive Ingredient

This example provides laboratory data showing stability of Clindagel(Example I) for at least 18 months at 25° C. Clindagel was tested forthe stability of the active ingredient, clindamycin phosphate, over timeat controlled room temperature (i.e., 25° C. and 60% relative humidity).A stability-indicating, high performance liquid chromatography assay wasused to assess remaining clindamycin phosphate potency, expressed asclindamycin, during the experiment. Based on the data shown in Table IX,Clindagel is projected to have a commercial shelf life of about 24months.

The estimated shelf life was calculated from the 95% confidence intervalaround the least squares fit to the available data. The projected shelflife is the time at which the drug potency reaches 90% of label claim(as allowed by the USP). The software used for the statistical analysisis named “SLIMStat+” and is sold by Metrics, Inc., P.O. Box 4035,Greenville, N.C. 27836, phone 252-752-3800.

TABLE IX Room Temperature Stability Assessment of Clindamycin Potency inClindagel ™, 1%. Percent Clindamycin by Weight 12 18 Initial 1 month 2months 6 months months months Clindamycin 1.028 1.017 1.009 1.004 0.9830.959 Phosphate Assay

Example VI Clindamycin Phosphate-Tretinoin Combination Composition

Section 1

This section of this example describes two gel compositions of theinvention in which the active ingredients are clindamycin phosphate andtretinoin.

Two pourable gel compositions containing a combination of clindamycinphosphate and tretinoin were made according to the invention. InFormulation A, the gel had a pH of about 5.5 and a viscosity of about6100 cP. In Formulation B, the gel exhibited a pH of about 4.7 and aviscosity of about 6,000 cP. See quantitative formulae in Table X. Thisexample illustrates the utility of our invention in the preparation ofphysically and chemically stable gel formulations.

TABLE X Quantitative compositions of two combination ClindamycinPhosphate/Tretinoin gel formulations: A B Component % w/w % w/wTretinoin  0.025  0.025 Clindamycin Phosphate  1.21 1.21 Propyl Gallate— 0.02 BHA  0.02 — Citric Acid — 0.05 Disodium Edetate  0.05 0.05Polysorbate 80 5.0 0.08 Propylene Glycol 5.0 — PEG 400 20.0  — Glycerin— 10.0  Methylparaben 0.1 0.15 CARBOPOL 981 0.5 0.5  Tromethamine (10%in water) QS to pH 5.5 QS to pH 4.5 Purified Water QSAD 100 QSAD 100

Method of preparation: Formula A

a. Combine the propylene glycol, polyethylene glycol 400, andpolysorbate 80. Add the tretinoin and stir to dissolve.

b. In a separate container dissolve the disodium edetate, methylparaben,and butylated hydroxyanisole in the purified water.

c. Add the clindamycin phosphate to the aqueous solution of step b andstir to dissolve.

d. Disperse the CARBOPOL 981 into the aqueous solution with high-speedstirring.

e. Add the tretinoin drug phase to the aqueous CARBOPOL dispersion withstirring and then add the tromethamine and mix to form a homogeneousgel.

Method of Preparation of Formula B

a. Combine the glycerin and polysorbate 80. Add the tretinoin and stirto wet and disperse.

b. In a separate container dissolve the propyl gallate, citric acid,disodium edetate, methylparaben, and butylated hydroxyanisole in thepurified water.

c. Add the clindamycin phosphate to the aqueous solution of step b andstir to dissolve.

d. Disperse the CARBOPOL 981 into the aqueous solution with high-speedstirring.

e. Add the tretinoin drug phase to the aqueous CARBOPOL dispersion withstirring and then add the tromethamine and mix to form a homogeneousgel.

Section 2

This Section of this example describes two additional compositions thatare slight modifications of Formulas A and B, wherein the preservativeshave been changed or adjusted. The formulas are given below. C issimilar to A, and D is similar to B.

TABLE XI C D Component % w/w % w/w Clindamycin Phosphate 1.24 1.24Tretinoin  0.025  0.025 Propyl Gallate — 0.02 BHA 0.02 — Citric Acid —0.05 Disodium Edetate 0.05 0.05 Methylparaben — 0.15 Propylparaben —0.03 Benzyl Alcohol 1   — Polysorbate 80 5   0.08 Propylene Glycol 5   —PEG 400 20    — Glycerin — 10    Tromethamine (10%) qs to pH 5.5 qs topH 4.5 CARBOPOL 981 0.5  0.5  Purified Water qsad 100 qsad 100

In making formula C, the 0.1% methylparaben preservative in Formula Awas replaced with 1.0% benzyl alcohol. In Formula D, 0.03% propylparabenwas added as an additional preservative (because the combination ofmethylparaben and propylparaben is sometimes a better preservativesystem). Methods of preparation:

Formula C is prepared similarly to Formula A, except that methylparabenwould be omitted from step “b,” and the benzyl alcohol would be added tostep “a.”

Formula D is prepared similarly to Formula B; propylparaben would beadded to step “b.”

The Formula C gel has a pH about 5.5 and a viscosity about 9000 cP. TheFormula D gel has a pH about 4.6 and a viscosity about 4100 cP.

Example VII Assessment of Chemical Stability of Tretinoin inFormulations A and B from Example VI

This example provides laboratory data showing the stability of tretinoinin two compositions of the invention under accelerated test conditions.

Tretinoin is known to be relatively unstable, therefore, the chemicalstability of these combination formulations was assessed in a 12-weekaccelerated stability study. The gels were packaged in amber glassvials, 8 grams each, and stored at 40° C. High performance liquidchromatography assays were performed initially and at 2, 4, and 12 weeksusing the method for tretinoin cream (USP 24, page 1684). Bothcompositions were found to retain their potency in this acceleratedstudy. Table XII summarizes the chemical stability results.

TABLE XII Accelerated Temperature (40° C.) Stability Assessment ofTretinoin Potency in Formulations A and B, Example VI. TretinoinConcentration TIME IN WEEKS (% w/w) 0 2 4 12 Formula A 0.0210 0.02280.0236 0.0231 Formula B 0.0236 0.0231 0.0234 0.0234

Example VIII Composition of Combination Gel Formulation

This example teaches how to modify a known commercial composition ofExample II to include tretinoin.

A combination gel formulation of tretinoin 0.025%, and clindamycin 1%was made by spatulating tretinoin powder and propyl gallate (anantioxidant to retard oxidative loss of tretinoin) into Cleocin*T gel(Example II). The quantitative formula is shown in Table XIII.

TABLE XIII Component Amount Tretinoin  0.0074 g Propyl Gallate  0.0145 gCleocin ® T gel 28.0000 g TOTAL 28.0219 g

The tretinoin and propyl gallate were accurately weighed, placed on aglass plate, and incorporated into the Cleocin®T gel with a spatula.During spatulation, the product was protected from light. The resultingproduct was a smooth, clear light yellow gel with a pH of 5.7 and aviscosity of about 20,000 cP.

Example IX Physical Stability Studies of the Compositions of Example VI(Formula A) and Example VIII

This example compares a composition of the invention (Example VI,Formula A) with a modified commercial composition (Example VIII) withregards to crystal growth.

The physical stability of Example VI, Formula A and Example VIII, wasassessed over a 4-week period at 5° C., 40° C. and 50° C. The stabilityevaluation was based on careful physical examination for description atinitial, 2 week and 4 week times. At study end, microscopic examinationwas performed to check for precipitation of tretinoin and crystalgrowth. As illustrated in the data summary below (Table XIV), themodified commercial formulation, Cleocin®T gel, was physically unstablecompared to a composition of the invention, Example VI (Formula A).

TABLE XIV Description: Clear Light Yellow Gel Initial 2 weeks 4 weeksExample VI (Formula A)  5° C. Clear Clear Clear - no crystals 40° C.Clear Clear Clear - no crystals 50° C. Clear Clear Clear - no crystalsExample VIII  5° C. Clear Hazy Hazy - Crystals to 1200 microns 40° C.Clear Translucent Hazy - Crystals to 1200 microns 50° C. ClearTranslucent Hazy - Crystals to 1200 microns

Example X

This example sets forth a lotion composition of this inventioncomprising two active ingredients: an antibiotic, i.e., clindamycinphosphate, and a retinoid, i.e., tretinoin. The components for thislotion are set forth in Table XIV.

TABLE XIV Component % w/w Clindamycin Phosphate 1.21 Tretinoin 0.025Stearyl Alcohol 5.00 Diisopropyl Adipate 6.00 PEG 40 Stearate (Myrj 52)2.00 Sorbitan Stearate (Span 60) 2.00 Butylated Hydroxytoluene 0.02Propylene Glycol 5.00 Methylparaben 0.15 Propylparaben 0.03 Citric Acid0.05 Disodium Edetate 0.10 CARBOPOL 981 0.10 Tromethamine (10%) qs pH5.5 Purified Water qsad 100

The viscosity of this composition is about 7,000 cP.

Method of Preparation:

a. Combine the propylene glycol and purified water. Add themethylparaben, propylparaben, citric acid, and disodium edetate and stirto dissolve.

b. Add the clindamycin phosphate to step “a” and stir to dissolve.

c. Add the Carpobol 981 to step “b” and stir to form a homogeneousdispersion.

d. Warm step “c” water phase to between 60° C. and 70° C.

e. Combine the stearyl alcohol, PEG 40 stearate, sorbitan stearate, andbutylated hydroxytoluene and warm to melt at between 60° C. to 70° C.

f. Add the tretinoin to the diisopropyl adipate and stir to dissolve.

g. With high-speed stirring add step “e” oil phase and step “f” drugphase sequentially to step “d” water phase and mix well.

h. Cool emulsion with continued stirring.

i. Add the tromethamine solution and stir to form a homogeneousemulsion. Cool to room temperature with continued stirring.

Example XI

This example sets forth a pourable gel composition of this inventionwhich gel contains a corticosteroid. Such formulation is suitable fortreating inflammatory skin conditions such as atopic dermatitis.

Component % by weight Halobetasol propionate, micronized 0.05 Docusatesodium 0.10 CARBOPOL ® 981 0.3 Propylene glycol 12 Methylparaben 0.1Propylparaben 0.02 Tromethamine QS pH 6.5 Purified water QSAD 100.00

The viscosity of this composition is about 6200 cP.

a. Dissolve the methylparaben and propylparaben in the propylene glycolat room temperature using a propeller mixer.

b. Weigh 70% of the formula weight of purified water and slowly add thesolution from step “a” while mixing with propeller mixer.

c. While continuing to mix, add CARBOPOL® 981 slowly to step “b.” Mix atroom temperature until a smooth and uniform dispersion is produced.

d. To 10% of the formula weight of water add the docusate sodium and mixuntil fully dissolved. To facilitate dissolution the mixture may bewarmed to 40-50° C., and then cooled to room temperature whendissolution is complete.

e. Disperse the micronized halobetasol propionate in step “d” with apropeller mixer or preferably a homogenizer of the rotor-stator type.

f. Add step “e” to step “c” using propeller mixer to uniformly dispersethe drug material.

g. Dissolve the tromethamine in 10 times its weight in purified water.While mixing, use the tromethamine solution to adjust the pH and thickenthe gel. Continue incremental additions until a pH of about 6.5 isattained.

h. Add water to make 100% of the batch size and mix until homogeneouswith a propeller-type mixer.

Example XII

This example sets forth yet another pourable gel composition of thisinvention. The formulation contains metronidazole for topicalapplication to the skin areas affected, for example, with rosacea.

Component % by weight Metronidazole 0.75 Methylparaben 0.12Propylparaben 0.03 CARBOPOL ® 981 0.25 Glycerin 5.00 Trolamine QS pH 8Purified Water QSAD 100

The viscosity of this composition is about 4700 cP.

a. Weigh 90% of the formula weight of purified water, metronidazole,glycerin, methyl-paraben and propylparaben into a suitable stainlesssteel container. Mix vigorously at room temperature until all componentsare dissolved. A propeller-type mixer is particularly suitable.

b. While continuing to mix, slowly add the CARBOPOL®. Mix until alump-free dispersion is attained.

c. Mix the trolamine with an equal part of purified water. Use thissolution to adjust the pH to about 8 with incremental additions whilemixing.

d. Add the balance of the purified water to make 100% and mix until ahomogeneous gel is produced.

Example XIII

This example sets forth a pourable gel composition of this inventionwhich gel contains a NSAID agent.

Component % by weight Naproxen 1.00 Octoxynol 9 0.10 CARBOPOL ® 981 0.30Propylene glycol 5.00 Glycerin 5.00 Benzyl alcohol 1.00 Sodiumhydroxide, 10% solution QS pH 3.0 to 3.5 Purified water QSAD 100.00

The viscosity of this composition is about 4200 cP.

a. Mix the benzyl alcohol, glycerin and propylene glycol together atroom temperature using a propeller mixer.

b. Weigh 70% of the formula weight of purified water and slowly add thesolution from step “a” while mixing with propeller mixer.

c. While continuing to mix, add CARBOPOL® 981 slowly to step “b.” Mix atroom temperature until a smooth and uniform dispersion is produced.

d. To 2-5% of the formula weight of water add the octoxynol 9 and mixuntil fully dissolved.

e. Disperse the naproxen in step “d” with a propeller mixer or ahomogenizer.

f. Add step “e” to step “c” using propeller mixer to uniformly dispersethe drug material.

g. While mixing, use the sodium hydroxide solution to adjust the pH.Continue incremental additions until a pH of 3.0 to 3.5 is attained.

g. Add water to make 100% of the batch size and mix until homogeneouswith a propeller-type mixer.

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

The invention now being fully described, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the appendedclaims.

What is claimed is:
 1. A topical aqueous gel composition having a pH ofabout 3 to about 9 and a viscosity of less than about 15,000 cP fortreating a skin disorder in a human subject, which composition consistsessentially of (a) a therapeutically-effective amount of at least onecompound useful for treating such disorder, (b) a hydrophilicpharmaceutically-acceptable, lightly cross-linked polyacrylic acidpolymer compatible with the compound, (c) a pharmaceutically-acceptablebase to adjust pH, (d) optionally a water miscible solvent, (e)optionally a preservative, and (f) water.
 2. The composition of claim 1,wherein the compound is an antibiotic, imidazole, retinoid,corticosteroid, or a non-steroidal anti-inflammatory drug (NSAID). 3.The composition of claim 2, wherein the compound is an antibiotic aloneor in combination with a corticosteroid or a retinoid.
 4. Thecomposition of claim 3, wherein the compound is an antibiotic alone. 5.The composition of claim 4, wherein the antibiotic is clindamycinphosphate.
 6. The composition of claim 5 having a pH of about 4.0 to7.0, which composition consists essentially of (a) about 0.5% to 2.0%w/w clindamycin phosphate, (b) about 0.1% to 0.4% w/w of the polymer,(c) the base to adjust pH, (d) about 15.0% to 25.0% w/w of a watermiscible solvent, (e) less than about 0.2% ww of a preservative, and (f)purified water in a quantity sufficient to make (QSAD) 100% w/w.
 7. Thecomposition of claim 6 having a pH of about 5.0 to 6.0, whichcomposition consists essentially of: (a) about 1.0 to 1.5% w/wclindamycin phosphate, (b) about 0.2% w/w of the polymer, (c) the baseto adjust pH, (d) about 15.0% w/w propylene glycol and about 5.0% w/wpolyethylene glycol 400 (e) about 0.1-0.15% w/w methylparaben, and (g)QSAD purified water to 100% w/w.
 8. The composition of claim 3, whereinan antibiotic is combined with a corticosteroid, the antibiotic isclindamycin phosphate, and the corticosteroid is desonide,hydrocortisone valerate, fluocinolone acetinide, hydrocortisonebutyrate, or triamcinolone acetonide.
 9. The composition of claim 3,wherein an antibiotic is combined with a retinoid, the antibiotic isclindamycin phosphate, and the retinoid is tretinoin.
 10. Thecomposition of claim 9 having a pH of about 4 to 7, which composition isa gel consisting essentially of (a) (i) about 0.5% to about 2.0% w/wclindamycin phosphate, and (ii) about 0.01% to about 0.05% w/wtretinoin; (b) about 0.1% to about 0.5% w/w of the polymer; (c) the baseto adjust pH; (d) about 10% to about 30% w/w of a water-misciblesolvent; (e) less than about 0.2% of a preservative; and (g) QSADpurified water 100% w/w.
 11. The composition of claim 1, wherein thecompound is a non-steroidal anti-inflammatory drug.
 12. The compositionof claim 11, wherein the compound is naproxen or diclofenac or apharmaceutically-acceptable salt thereof.
 13. The composition of claim2, having a corticosteroid as the sole active agent.
 14. The compositionof claim 13, wherein the corticosteroid is diflorasone diacetate,fluticasone propionate, halobetasol propionate, or budesonide.
 15. Thecomposition of claim 14, wherein the corticosteroid is halobetasolpropionate.
 16. The composition of claim 1 in combination with acontainer that accurately administers a portion of the composition fortopical administration to a patient.
 17. The composition of claim 16 incombination with labeling instructions for use in treating the skindisorder.
 18. A method for treating a skin disorder in a human subject,which method comprises topically administering an aqueous gelcomposition having a pH of about 3 to about 9 and a viscosity of lessthan about 15,000 cP to an affected area of the subject's skin havingsuch disorder in an amount and for a period of time sufficient toimprove the skin disorder, wherein the composition consists essentiallyof (a) a therapeutically-effective amount of at least one compounduseful for treating such disorder, (b) a hydrophilic,pharmaceutically-acceptable lightly cross-linked polyacrylic acidpolymer compatible with the pharmaceutical active material, (c) apharmaceutically-acceptable base to adjust pH (d) optionally a watermiscible solvent, (e) optionally a preservative, and (f) water.
 19. Themethod of claim 18, wherein the skin disorder is an inflammatory skindisorder, acne, or rosacea.
 20. The method of claim 19, wherein thecomposition is administered once a day for the period of time sufficientto improve the skin disorder.
 21. The method of claim 19, wherein theskin disorder is acne.
 22. The method of claim 19, wherein the compoundof the composition is an antibiotic, imidazole, retinoid,corticosteroid, or NSAID.
 23. The method of claim 22, wherein thecompound is an antibiotic alone or in combination with a corticosteroid,or a retinoid.
 24. The method of claim 23, wherein the compound is anantibiotic alone.
 25. The method of claim 24, wherein the antibiotic isclindamycin phosphate.
 26. The method of claim 18, wherein thecomposition has a pH of about 4.0 to 7.0 and consists essentially of (a)about 0.5% to 2.0% w/w clindamycin phosphate, (b) about 0.1% to 0.4% w/wof the polymer, (c) a base to adjust pH, (d) about 15% to 25.0% w/w of awater miscible solvent, (e) less than about 0.2% w/w of a preservative,(f) QSAD purified water to 100% w/w.
 27. The method of claim 26, whereinthe composition has a pH of about 5.0 to 6.0 and has the followingcomponents: (a) about 1.0 to 1.5% w/w clindamycin phosphate, (b) about0.2% ww of the polymer, (c) a base to adjust pH, (d) about 15% w/w %propylene glycol and 5 w/w % polyethylene glycol 400, (e) about0.1-0.15% w/w methylparaben, and (f) QSAD purified water to 100% w/w.28. The method of claim 22, wherein the compound is an antibiotic incombination with a corticosteroid.
 29. The method of claim 28, whereinthe antibiotic is clindamycin phosphate and the corticosteroid isdesonide, hydrocortisone valerate, fluocinolone acetonide,hydrocortisone butyrate, or triamcinolone acetonide.
 30. The method ofclaim 23, wherein the antibiotic is clindamycin phosphate and iscombined with tretinoin.
 31. The method of claim 30, wherein thecomposition is a gel having a pH of about 4 to 7, consisting essentiallyof (a) (i) about 0.5% to about 2.0% w/w clindamycin phosphate, and (ii)about 0.01% to about 0.05% w/w tretinoin; (b) about 0.1% to about 0.5%w/w of the polymer; (c) the base to adjust pH; (d) about 10% to about30% w/w of a water-miscible solvent; (e) less than about 0.2% of apreservative; and (g) QSAD purified water 100% w/w.
 32. The method ofclaim 18, wherein the compound is an NSAID.
 33. The method of claim 32,wherein the compound is diclofenac or naproxen or a pharmaceuticallyacceptable salt thereof.
 34. The method of claim 19, wherein compositioncontains a corticosteroid as the sole active agent.
 35. The method ofclaim 34, wherein the corticosteroid is diflorasone diacetate,fluticasone propionate, halobetasol propionate, or budesonide.
 36. Themethod of claim 35, wherein the corticosteroid is halobetasolpropionate.
 37. A method of preparing an aqueous gel composition havinga viscosity of less than about 15,000 cP and a pH of about 3 to 9 usefulfor treating a skin disorder in a human subject, which method comprises(a) combining water with a therapeutically-effective amount of at leastone compound useful for treating such disorder and a hydrophilic,pharmaceutically-acceptable, lightly cross-linked polyacrylic acidpolymer compatible with the compound, (b) adjusting the pH to about 3 to9, and (c) optionally combining a water-miscible solvent and apreservative to form the composition.
 38. The method of claim 37,wherein the compound is an antibiotic, imidazole, retinoid,corticosteroid, or a NSAID.
 39. The method of claim 38, wherein thecompound is an antibiotic alone or in combination with a corticosteroidor a retinoid.
 40. The method of claim 39, wherein the compound is anantibiotic alone.
 41. The method of claim 40, wherein the antibiotic isclindamycin phosphate.
 42. The method of claim 41, wherein thecomposition has a pH of about 4 to 7, and consists essentially of (a)about 0.5% to 2.0% w/w clindamycin phosphate, (b) about 0.1% to 0.4% w/wof the polymer, (c) the base to adjust pH, (d) about 15.0% to 25.0% w/wof a water miscible solvent, (e) less than about 0.2% ww of apreservative, and (f) QSAD purified water to 100% w/w.
 43. The method ofclaim 42, wherein the composition has a pH of about 5 to 6, and consistsessentially of: (a) 1.0 to 1.5% w/w clindamycin phosphate, (b) 0.2% w/wof the polymer, (c) the base to adjust pH, (d) 15.0% w/w propyleneglycol and 5.0% w/w polyethylene glycol 400 (e) 0.1-0.15% w/wmethylparaben, and (f) QSAD purified water to 100% w/w.
 44. The methodof claim 39, wherein the antibiotic is combined with a corticosteroid,the antibiotic is clindamycin phosphate, and the corticosteroid isdesonide, hydrocortisone valerate, fluocinolone acetinide,hydrocortisone butyrate, or triamcinolone acetonide.
 45. The method ofclaim 39, wherein the antibiotic is combined with a retinoid, theantibiotic is clindamycin phosphate, and the retinoid is tretinoin. 46.The method of claim 45, wherein the composition is a gel having a pH ofabout 4 to 7 and consists essentially of (a) (i) about 0.5% to about2.0% w/w clindamycin phosphate, and (ii) about 0.01% to about 0.05% w/wtretinoin; (b) about 0.1% to about 0.5% w/w of the polymer; (c) the baseto adjust pH; (d) about 10% to about 30% w/w of a water-misciblesolvent; (e) less than about 0.2% of a preservative; and (f) QSADpurified water 100% w/w.
 47. The method of claim 38, wherein thecompound is a NSAID.
 48. The method of claim 47, wherein the compound isnaproxen or diclofenac or a pharmaceutically-acceptable salt thereof.49. The method of claim 38, wherein the composition has a corticosteroidas the sole active agent.
 50. The method of claim 49, wherein thecorticosteroid is diflorasone diacetate, fluticasone propionate,halobetasol propionate, or budesonide.
 51. The method of claim 50,wherein the corticosteroid is halobetasol propionate.
 52. The method ofclaim 37, which method further comprises placing the composition in acontainer from which drops are accurately administered for topicaladministration to a patient.
 53. The method of claim 52, which methodfurther comprises combining the container with labeling instructions foruse in treating the skin disorder.
 54. The composition of claim 13,wherein the corticosteroid is desonide.
 55. The composition of claim 54,wherein the desonide is present at about 0.01% w/w to about 1 0% w/w.56. The method of claim 34, wherein the corticosteroid is desonide. 57.The method of claim 56, wherein the desonide is present at about 0.01%w/w to about 1.0% ww.
 58. The method of claim 49, wherein thecorticosteroid is desonide.
 59. The method of claim 58, wherein thedesonide is present at about 0.01% w/w to about 1.0% ww.